Abstract Circadian rhythm and sleep disruptions are a defining feature of psychiatric disorders like Bipolar disorder (BP), schizophrenia (SCZ) and major depressive disorder (MDD). These disruptions to normal rhythmicity include altered sleep/wake cycles, diurnal patterns of hormone levels, and circadian gene expression in peripheral samples. Moreover, disruptions to the normal sleep/wake cycle often precipitate mood and psychotic episodes, and may contribute to deficits in cognitive function. A number of treatments for psychiatric disorders may derive their efficacy through stabilization or amplification of molecular rhythms in the brain. However, the molecular rhythm changes that occur in human brain in subjects with psychiatric diseases remain largely unknown. Measurement of rhythmic gene expression in the human brain is now possible. Two recent studies, including one from our group, demonstrated molecular rhythmicity on a genome-wide scale by employing a ?time of death? analysis to order postmortem human brain samples around a 24-hour cycle. The first study by Li et al. found that MDD subjects had major disruptions in molecular rhythms across six different brain regions, including prefrontal cortex (PFC) area 46 and subgenual cingulate (SGC) area 25, compared with comparison subjects. Using the same approach in a cohort of 146 control subjects (ranging in age from 16 to 96 years), we found that two PFC regions exhibited highly significant patterns of rhythmic gene expression. Moreover, we found that normal aging was associated with a significant loss of rhythmicity in a number of transcripts and a surprising gain of rhythmicity in others. Here we plan to study psychiatric disease populations. In preliminary studies of subjects with SCZ and BP we find that SCZ is associated with a marked loss of molecular rhythms of core clock genes in PFC area 46, whereas BP is associated with a phase advance in rhythms in this region. Moreover, we measured molecular rhythms in isolated cell types (pyramidal cells and parvalbumin (PV) containing cells) from specific cortical layers (3 and 5) of control subjects and subjects with SCZ. Our data suggests that there are striking differences in the identity and timing of rhythmic genes in these individual cell types in control subjects. Moreover, subjects with SCZ do not simply have a loss of rhythmicity in these cells, but have a totally different rhythmic profile, suggesting that there are differences in the transcriptional complex that governs molecular rhythmicity in these cells. In this study we will determine changes in molecular rhythms associated with psychiatric diagnoses or specific clinical features such as psychosis, mood and suicide independent of diagnosis in areas 46 and 25 (Aim #1). We will then determine the layer and cell type specificity of changes in the PFC in these same subjects (Aim #2). Then we will test the functional relevance of these molecular rhythms disruptions in specific cell types to behavior in mouse models (Aim #3). These pioneering studies of molecular rhythmicity in the human brain will be central to our understanding of how rhythm disruptions are connected in such a profound way to psychiatric diseases.